Background
Multicenter prospective open-label randomized phase 2 noninferiority trial (NCT04669210), N=128 adults with AML or ALL in complete remission undergoing unrelated or haploidentical donor alloHCT, randomized 1:1 (stratified by donor type and disease risk index). Compared calcineurin-free PTCy + ruxolitinib (PTCy-Ruxo) vs conventional PTCy + tacrolimus + MMF (PTCy-Tac-MMF).
Interventions and follow up
Arm A (PTCy-Ruxo): Cyclophosphamide 50 mg/kg IV days +3/+4 + ruxolitinib 5 mg TID during conditioning and days +5 to +21, then 5 mg BID days +22 to +150 (no calcineurin inhibitor, no MMF).
Arm B (PTCy-Tac-MMF): Cyclophosphamide 50 mg/kg IV days +3/+4 + tacrolimus (target 5–15 ng/mL) + MMF 30 mg/kg/day (10/10 HLA) or 45 mg/kg/day (<10/10 HLA) days +5 to +35.
Primary endpoint: Cumulative incidence of grade II–IV acute GVHD at day +125 (noninferiority margin 10%, one-sided α 2.5%).
mFollow up: 2 years.
Arm B (PTCy-Tac-MMF): Cyclophosphamide 50 mg/kg IV days +3/+4 + tacrolimus (target 5–15 ng/mL) + MMF 30 mg/kg/day (10/10 HLA) or 45 mg/kg/day (<10/10 HLA) days +5 to +35.
Primary endpoint: Cumulative incidence of grade II–IV acute GVHD at day +125 (noninferiority margin 10%, one-sided α 2.5%).
mFollow up: 2 years.
Results
Grade II–IV aGVHD (day +125): 12.9% (PTCy-Ruxo) vs 21.2% (PTCy-Tac-MMF); risk difference −8.3% (95% CI −21.2% to +4.6%); noninferiority P=.0041 (superiority P=.20).
Moderate-severe cGVHD (2-yr): 24.2% vs 39.5%; risk difference −15.2% (95% CI −31.1% to +0.7%); noninferiority P=.0012 (superiority P=.09).
2-yr OS: 80.6% vs 72.5%; P=.28.
GRFS: 61.3% vs 48.1%; P=.19.
NRM / relapse: NR.
Moderate-severe cGVHD (2-yr): 24.2% vs 39.5%; risk difference −15.2% (95% CI −31.1% to +0.7%); noninferiority P=.0012 (superiority P=.09).
2-yr OS: 80.6% vs 72.5%; P=.28.
GRFS: 61.3% vs 48.1%; P=.19.
NRM / relapse: NR.
Adverse events
Renal: Grade 2–4 acute kidney injury 1.6% (PTCy-Ruxo) vs 12.1%; P=.02.
Endothelial: Endothelial complications 1.6% vs 13.6%; P=.01.
Graft function: Severe poor graft function 21.1% vs 42.6%; P=.01. Cytopenias expected with both regimens; no differences in infectious complications reported.
Endothelial: Endothelial complications 1.6% vs 13.6%; P=.01.
Graft function: Severe poor graft function 21.1% vs 42.6%; P=.01. Cytopenias expected with both regimens; no differences in infectious complications reported.
Conclusions
PTCy-Ruxo was noninferior to standard PTCy-Tac-MMF for prevention of grade II–IV acute GVHD at day +125 in unrelated and haploidentical donor alloHCT, with a similarly favorable cGVHD profile and a clearly improved safety profile (less AKI, fewer endothelial complications, less severe poor graft function). PTCy-Ruxo warrants further exploration as a calcineurin-free alternative on a PTCy backbone.
Key Limitations
Single-country (Russia) phase 2 trial — external validity awaits multinational replication. Restricted to AML/ALL in complete remission; does not address lymphoma, myeloma, or MDS. Both arms received PTCy, so ruxolitinib-alone efficacy is not addressed. Powered for noninferiority, not superiority — numerical OS/GRFS/cGVHD advantages did not reach significance. Optimal ruxolitinib duration beyond day +150 not addressed.
Clinical Context
First randomized comparison of two PTCy-anchored prophylaxis regimens, supporting a calcineurin-sparing strategy in alloHCT. Findings parallel single-arm ruxolitinib maintenance data (DeFilipp et al, Blood 2025) and reinforce interest in JAK1/2 inhibition for GVHD prevention. PTCy-Tac-MMF remains the established standard on the strength of BMT CTN 1703; PTCy-Ruxo may evolve into an alternative for patients with calcineurin-related toxicities, particularly TMA-prone or renally fragile recipients, within ASTCT frameworks.